title: Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis.
abstract: Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of the PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we investigated the role of PARP-1 in liver inflammation and fibrosis using acute and chronic models of carbon tetrachloride (CCl4 )-induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl4 -induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL-induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis, increased nitrative stress and PARP activation was noted.
  
  
  CONCLUSIONS
  The reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential.
authors.affiliation: Laboratory of Physiological Studies, National Institutes of Health/NIAAA, Bethesda, MD, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Rajesh
authors.forename: Zongxian
authors.initials: Z
authors.lastname: Cao
authors.forename: Béla
authors.initials: B
authors.lastname: Horváth
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Katalin
authors.initials: K
authors.lastname: Erdelyi
authors.forename: Eileen
authors.initials: E
authors.lastname: Holovac
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wang
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.forename: Nabila
authors.initials: N
authors.lastname: Hamdaoui
authors.forename: Fouad
authors.initials: F
authors.lastname: Lafdil
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
authors.forename: A Hamid
authors.initials: AH
authors.lastname: Boulares
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D055166:Hepatic Stellate Cells / Q000502:physiology; D006505:Hepatitis / Q000188:drug therapy / Q000209:etiology*; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D002251:Carbon Tetrachloride; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases